C1QTNF1 Human

Molecular Structure and Biochemical Properties

C1QTNF1 is a 35 kDa protein that contains a distinctive collagen-like region and one C1q-like domain, similar to other members of the C1q and TNF-related protein (CTRP) family . The mature human C1QTNF1 spans from amino acid positions Arg26 to Pro281 and shares approximately 80% amino acid sequence identity with its mouse and rat orthologs, indicating a high degree of evolutionary conservation .

The protein features a C-terminal globular domain that facilitates multimerization and receptor binding, enabling it to form both homotrimers and heterotrimers with other proteins including adiponectin . This structural arrangement is critical for its functional versatility across different tissues and biological processes.

Commercial recombinant human C1QTNF1 protein formulations are available as lyophilized preparations from a filtered solution in HEPES and NaCl, typically reconstituted at 250 μg/mL in PBS .

Tissue Expression and Distribution

C1QTNF1 exhibits a defined pattern of tissue expression with significant implications for its biological roles. The protein is prominently expressed in multiple tissues including:

Expression Profile in Human Tissues

Human C1QTNF1 is expressed in various tissues, with particularly notable presence in:

1. Adipose tissue - a primary site of production

2. Heart muscle - detected in sarcoplasm of cardiomyocytes

3. Vascular tissues - including arterial walls

4. Skeletal muscle

5. Adrenal cortex - where it influences hormone production

Immunohistochemical analysis has confirmed the protein's presence in human heart tissue, specifically localized to the sarcoplasm in cardiomyocytes . Western blot analysis of human heart (atrium) tissue lysates has also demonstrated the expression of C1QTNF1 at the expected molecular weight of approximately 35 kDa .

The expression of C1QTNF1 shows significant regulation under various physiological and pathological conditions. Studies have demonstrated that inflammatory cytokines and oxidized low-density lipoprotein (LDL) can upregulate C1QTNF1 expression in atherosclerotic plaques and adipose tissue .

Physiological Functions of C1QTNF1

C1QTNF1 serves as a multifunctional protein with diverse roles across several physiological systems, from metabolic regulation to cardiovascular protection.

Metabolic Regulation

C1QTNF1 is increasingly recognized as an important regulator of energy metabolism and glucose homeostasis:

1. Glucose metabolism: Studies in animal models have demonstrated that C1QTNF1 reduces glucose concentration and enhances insulin sensitivity . It promotes glucose uptake in adipocytes, myotubes, and hepatocytes through activation of the AMPK signaling pathway .

2. Lipid metabolism: The protein promotes fatty acid oxidation and energy expenditure in skeletal muscle, contributing to improved metabolic efficiency .

3. Weight regulation: Elevated concentrations of C1QTNF1 have been shown to reduce weight gain and diet-induced insulin resistance in experimental models .

Cardiovascular Effects

C1QTNF1 demonstrates significant cardiovascular protective effects through several mechanisms:

1. Myocardial protection: Systemically administered C1QTNF1 can limit tissue damage following myocardial infarction by attenuating ischemia-reperfusion injury .

2. Anti-hypertrophic activity: Human recombinant C1QTNF1 improves cardiac hypertrophy induced by angiotensin II infusion and pressure overload through activation of the AMPKα pathway .

3. Platelet function: C1QTNF1 inhibits platelet aggregation by blocking von Willebrand factor binding to collagen, potentially reducing thrombotic risk .

4. Blood pressure regulation: During dehydration, increased C1QTNF1 concentration helps maintain normotension, suggesting a role in blood pressure homeostasis .

Inflammatory and Tissue Remodeling Functions

C1QTNF1 plays complex roles in inflammation and tissue remodeling:

1. Vascular remodeling: Research indicates that C1QTNF1 can prevent neointimal formation after arterial injury, demonstrating a protective effect in vascular remodeling .

2. Chondrocyte regulation: The protein participates in the proliferation and maturation of chondrocytes, indicating a role in cartilage development and maintenance .

3. Aldosterone regulation: C1QTNF1 stimulates aldosterone synthesis in the adrenal cortex by affecting aldosterone synthase expression, implying a role in fluid and electrolyte balance .

Pathophysiological Implications

The dysregulation of C1QTNF1 has been implicated in various pathological conditions, highlighting its clinical significance.

Metabolic Disorders

C1QTNF1 levels are altered in several metabolic disorders:

1. Obesity: Circulating levels of C1QTNF1 are elevated in obesity, suggesting a potential compensatory mechanism or contribution to related pathologies .

2. Type 2 diabetes: Increased C1QTNF1 concentrations have been observed in patients with type 2 diabetes and show associations with insulin sensitivity in Chinese subjects .

3. Metabolic syndrome: Alterations in C1QTNF1 levels are associated with components of metabolic syndrome including hypertension and insulin resistance .

Cardiovascular Diseases

C1QTNF1 demonstrates complex roles in cardiovascular pathology:

1. Atherosclerosis: Despite its protective effects in some contexts, C1QTNF1 can also promote atherosclerosis, with increased concentrations correlating with higher cardiovascular risk in patients with coronary atherosclerosis .

2. Inflammatory responses: In vascular smooth muscle cells, C1QTNF1 induces the expression of proinflammatory cytokines, potentially contributing to vascular inflammation .

3. Coronary artery disease: Serum levels of C1QTNF1 are closely associated with coronary artery disease, suggesting its potential as a biomarker .

4. Heart failure: Associations have been observed between C1QTNF1 levels in human plasma and epicardial adipose tissues and congestive heart failure .

Oncological Implications

Emerging evidence suggests roles for C1QTNF1 in cancer biology:

1. Kidney cancer: High expression of C1QTNF1 is associated with kidney renal clear cell carcinoma (KIRC) progression and immune infiltration, suggesting its potential involvement in renal cancer pathogenesis .

2. Glioblastoma: Increased C1QTNF1 levels correlate with the progression of the neoplastic process in patients with glioblastoma, indicating a potential role in brain tumor biology .

3. Osteosarcoma: Studies involving C1QTNF1-AS1 (an antisense lncRNA related to C1QTNF1) have shown that its silencing leads to substantial increases in ATP production and lactate production in osteosarcoma cells, suggesting metabolic influences in cancer cells .

Molecular Interactions and Signaling Pathways

C1QTNF1 interacts with multiple proteins and activates various signaling pathways to exert its biological effects.

Protein-Protein Interactions

Several key protein interactions have been identified:

1. C1QTNF1 has been shown to interact with Arginine vasopressin receptor 2 (AVPR2), potentially influencing water reabsorption and blood pressure regulation .

2. STRING database analysis reveals interactions with multiple proteins including C1QTNF6, ERFE, COL21A1, C1QTNF12, TNF, C1QL1, COL4A1, COL4A2, and C1QL3 .

3. C1QTNF1 binds to BAI3 (brain-specific angiogenesis inhibitor 3), consistent with reported interactions between BAI3 and other C1qL proteins .

Signaling Cascades

C1QTNF1 activates several signaling pathways:

1. AMPK pathway: C1QTNF1 attenuates angiotensin II-induced cardiac hypertrophy via activation of the AMPKα pathway, demonstrating cardioprotective effects .

2. PI3K-Akt signaling: This pathway appears to mediate some of the metabolic effects of C1QTNF1, particularly in glucose metabolism regulation .

3. Inflammatory signaling: C1QTNF1 can induce expression of proinflammatory cytokines in various cell types, suggesting activation of inflammatory signaling cascades .

Diagnostic and Therapeutic Potential

The diverse functions of C1QTNF1 suggest several potential clinical applications.

Biomarker Applications

C1QTNF1 shows promise as a biomarker for several conditions:

1. Cardiovascular disease: Serum levels of C1QTNF1 are closely associated with coronary artery disease, suggesting utility as a diagnostic or prognostic marker .

2. Metabolic disorders: Altered C1QTNF1 levels in obesity, diabetes, and metabolic syndrome indicate potential as a biomarker for these conditions .

3. Kidney disease: In patients with chronic kidney disease, increased C1QTNF1 levels are associated with lesser disease progression, suggesting value in monitoring renal function .

4. Cancer: Correlations between C1QTNF1 expression and cancer progression (particularly in glioblastoma and kidney cancer) suggest potential as a tumor marker .

Therapeutic Opportunities

The biological activities of C1QTNF1 present several therapeutic opportunities:

1. Metabolic disorders: The ability of C1QTNF1 to enhance insulin sensitivity, promote glucose uptake, and reduce weight gain suggests potential applications in treating type 2 diabetes and obesity .

2. Cardiovascular protection: The cardioprotective effects, particularly in limiting myocardial infarction damage and improving cardiac hypertrophy, indicate potential for heart failure treatments .

3. Vascular disease: The role of C1QTNF1 in preventing neointimal formation after arterial injury suggests applications in preventing restenosis following vascular procedures .

Detection and Quantification Techniques

Several methods are available for studying C1QTNF1:

1. ELISA assays: Commercially available enzyme-linked immunosorbent assays enable measurement of serum CTRP1 levels in clinical and research settings .

2. Western blot: Anti-human CTRP1/C1qTNF1 monoclonal antibodies (such as Clone #395520) are available for protein detection in tissue lysates .

3. Immunohistochemistry: Validated protocols exist for detecting C1QTNF1 in tissue sections, particularly using monoclonal antibodies in paraffin-embedded samples .

Research Tools

Key resources for C1QTNF1 research include:

1. Recombinant proteins: Purified recombinant human C1qTNF1 protein is commercially available (e.g., R&D Systems product 9268-TN-050), enabling functional studies .

2. Antibodies: Human CTRP1/C1qTNF1 antibodies for various applications including Western blot and immunohistochemistry (e.g., MAB10445) .

3. Genetic databases: Information on C1QTNF1 gene location and details are available through resources like the UCSC Genome Browser .